Programmed cell death (PCD) pathways are found in many phyla, ranging from developmentally programmed apoptosis in animals to cell-autonomous programmed necrosis pathways that limit the spread of biotrophic pathogens in multicellular assemblies. Prominent examples for the latter include animal necroptosis and pyroptosis, plant hypersensitive response (HR), and fungal heterokaryon incompatibility (HI) pathways. PCD pathways in the different kingdoms show fundamental differences in execution mechanism, morphology of the dying cells, and in the biological sequelae. Nevertheless, recent studies have revealed remarkable evolutionary parallels, including a striking sequence relationship between the "HeLo" domains found in the pore-forming components of necroptosis and some types of plant HR and fungal HI pathways. Other PCD execution components show cross-kingdom conservation as well, or are derived from prokaryotic ancestors. The currently available data suggest a model, wherein the primordial eukaryotic PCD pathway used proteins similar to present-day plant R-proteins and caused necrotic cell death by direct action of Toll and IL-1 receptor (TIR) and HeLo-like domains. Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.